Rheumatoid arthritis (RA) and Systemic Lupus Erythematosus (SLE) are debilitating autoimmune diseases afflicting millions of Americans;they also cause a significant economic burden. Recently both diseases have been associated with aberrant T helper-17 (Th17) responses. These adaptive immune response cells are critical in defense against many extracellular bacteria and fungi, but they have also been implicated in a number of inflammatory and autoimmune diseases, including RA and SLE. IL-17 (aka IL-17A) is the signature cytokine of Th17 cells and the functional significance of this cytokine in arthritis has been revealed with a mouse model. Mice lacking IL-17A exhibit an ameliorated pathology in the collagen-induced arthritis (CIA) model. However, there is some evidence that other members of the IL-17 family may contribute to arthritis, including the closely related IL-17F. It is therefore imperative to explore whether blocking the signaling by all members of this cytokine family could be a therapeutic strategy in RA. The CIKS adaptor protein is essential to signaling by IL-17 cytokines. To test whether this adaptor might be a useful therapeutic target, we generated mice lacking CIKS and subjected them to collagen-induced arthritis. In FY 2011 we discovered that these mice are totally protected from CIA. This result provides a proof-of-principle indicating that CIKS is a possible target for therapeutic intervention in rheumatoid arthritis. Regarding the functional relevance of IL-17 cytokines in SLE, it has been demonstrated that IL-17 contributes to the production of autoantibodies in a spontaneous mouse model of lupus. However, it has not been addressed whether IL-17 or other members of this family play a critical role in the ultimately fatal outcome of lupus in mouse models. Furthermore, it is not known if targeting the signaling pathway of these cytokines could be a useful therapeutic strategy. In FY 2011 we have obtained initial evidence that lupus-prone mice lacking CIKS or IL-17 were able to survive much longer and that kidney pathology was greatly ameliorated, the likely cause for the extended survival of these mice. These findings provide the first proof-of-principle of the notion that IL-17 and its signaling pathway are possible targets for therapeutic intervention in severe, life-threating cases of SLE.